WO2002000615A2 - Procede d'isolation de lovastatine - Google Patents

Procede d'isolation de lovastatine Download PDF

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Publication number
WO2002000615A2
WO2002000615A2 PCT/IB2001/001087 IB0101087W WO0200615A2 WO 2002000615 A2 WO2002000615 A2 WO 2002000615A2 IB 0101087 W IB0101087 W IB 0101087W WO 0200615 A2 WO0200615 A2 WO 0200615A2
Authority
WO
WIPO (PCT)
Prior art keywords
lovastatin
acid
formula
lactonization
aqueous medium
Prior art date
Application number
PCT/IB2001/001087
Other languages
English (en)
Other versions
WO2002000615A3 (fr
Inventor
Parveen Kumar
S. Raman
Pardeep Narula
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to BR0112024-7A priority Critical patent/BR0112024A/pt
Priority to PL01359560A priority patent/PL359560A1/xx
Priority to AU2001264173A priority patent/AU2001264173A1/en
Priority to CA002412566A priority patent/CA2412566A1/fr
Priority to EP01938499A priority patent/EP1299340A4/fr
Priority to US10/311,944 priority patent/US7052886B2/en
Priority to HU0301423A priority patent/HUP0301423A2/hu
Publication of WO2002000615A2 publication Critical patent/WO2002000615A2/fr
Publication of WO2002000615A3 publication Critical patent/WO2002000615A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • the present invention relates to a process for the preparation and isolation of the hypolipaemic active substance lovastatin in substantially pure form having a purity of at least 95% which comprises lactonizing the mevinolinic acid of Formula II
  • HMG-CoA reductase inhibitors Lovastatin, Pravastatin, Simvastatin, Mevastatin, Atorvastatin and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as anti- hypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus; others are obtained by treating the fermentation products using the method of chemical synthesis or they are the product of total chemical synthesis.
  • Lovastatin is the first of the statins to be used widely and is manufactured by a fermentation-based process. It is produced as a secondary metabolite of the fungus Aspergillus terreus (U.S. Patent No. 4,231 ,938) deposited in American Type Culture Collection under Nos. ATCC
  • Chemically lovastatin is 1 ,2,6,7,8,8a-hexahydro- ⁇ , ⁇ -dihydroxy-2,6-
  • lovastatin is an acid, which is chemically 1 ,2,6,7,8,8a-
  • CoA reductase inhibitors has provided a need for the development of high yielding processes for production of fermentation-based statins.
  • the techniques to improve the processes include, but are not limited to, improving the producer microorganism, scale-up of the process, improving the culture medium or simplifying the downstream recovery process.
  • lovastatin is present mostly in its hydroxy acid form, mevinolinic acid.
  • the isolation of lovastatin from the fermentation broth can be categorised into two routes in the prior art processes.
  • the first route comprises of solvent extraction of mevinolinic acid and isolation of ammonium salt of mevinolinic acid as an intermediate and its further lactonization to lovastatin (U.S. Patent No. 4,319,039).
  • the second route comprises of solvent extraction of mevinolinic acid, lactonization in the solvent phase and isolation as lovastatin (PCT publication
  • the isolation of lovastatin as disclosed in EP 033536 comprises of extraction of the broth with ethyl acetate.
  • the extract is concentrated by vacuum distillation followed by lactonization in toluene at 106°C for 2 hours. After the lactonization is complete, the solution is concentrated to a small volume and then subjected to column chromatography using solvents like ethyl acetate or n-hexane and the collected fractions are again concentrated in vacuum and then pure lovastatin crystallizes in the lactone form.
  • Both the routes may employ a final purification step to obtain lovastatin of pharmacopoeial grade.
  • the process for the isolation and purification of anti-hypercholesterol- emic agents disclosed in the earlier patents have certain inherent disadvantages and involves a number of steps which include multiple solvent extractions, chromatography, lactonization and crystallization methods. Although, the purity of the final product obtained by these procedures is of pharmacopoeial standards yet, the yields of the desired product are relatively low. In addition, they require both large amounts of organic solvents and correspondingly large equipment suited for these quantities.
  • the second route involves lactonization at higher temperature in the solvent phase necessitating elaborate purification step(s) for removal of undesirable impurities generated during the lactonization step.
  • the process in addition, also yields higher quality product.
  • the present invention solves the drawbacks of the processes known in the prior art as it enables to obtain the pure lovastatin by a process, which process is less time consuming and provides higher yields using fewer number of solvents.
  • the process is more nature friendly, is not demanding in terms of space and energy and thus, enables an economical large scale production.
  • the present invention specifically describes a process for effecting the lactonization of mevinolinic acid of Formula II
  • lovastatin is derived from the fermentation broth which comprises of the microorganism preferably a fungus belonging to the genus Aspergillus, preferably Aspergillus terreus (ATCC 20542) or its hyperproducer thereof.
  • the process comprises lowering the pH of the fermented broth containing lovastatin, present mostly in the form of mevinolinic acid to 2.0 to 3.0, and incubating the broth for about 20-60 hours at a temperature from about 40-60°C affecting the lactonization of mevinolinic acid and recovering the corresponding lovastatin from the solution thereof.
  • the acid for lowering the pH may be selected from the commonly used acids, preferably the mineral acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • the broth is incubated for 24 hours. In a further preferred embodiment, the broth is incubated at a temperature in the range of 40-60°C, most preferable being 50-60°C.
  • lovastatin is isolated from the solution by extracting it with a solvent followed by concentration of solvent, crystallization and drying the product.
  • Solvent which may be used is generally selected from esters such as ethyl acetate, butyl acetate or aromatic hydrocarbons such as toluene. Methods known in the art may be used with the process of this invention to enhance any aspect of this process.
  • lovastatin obtained may further be purified. The purification can be such as recrystallization from solvents. DETAILED DESCRIPTION OF THE INVENTION
  • EXAMPLE 1 To 6.2 L of fermentation broth, 0.80 L of dilute sulfuric acid (2N) was added to bring the pH to 2.1. The acidified broth was heated to about 50°C and was stirred at 50 - 60°C for about 24 hours. 90 % of the acid form was converted to lactone form as monitored by High Pressure Liquid Chromatography.
  • the broth was filtered and the mycelial cake was extracted with 7.5 L of toluene.
  • the toluene extract was washed with 1.3 L of 5 % w/v sodium bicarbonate solution and 0.65 L of demineralised water.
  • the washed toluene extract was concentrated under vacuum at about 60°C, to a volume of about 160-200 mL.
  • the concentrate was cooled to 5-7°C and stirred further for 1 hour.
  • the slurry was then filtered and the cake was washed with 50 mL of pre-cooled (5-10°C) toluene.
  • the wet cake was dried at 40°C under vacuum for 16 hours. 25.6 g of Lovastatin with a chromatographic purity of more than 95% was obtained.
  • EXAMPLE 2 To 12 L of fermentation broth, 1.40 L of dilute nitric acid (10 %) was added to bring the pH to 2.2. The acidified broth was heated to about 50°C and was stirred at this temperature for about 48 hours. 90 % of the acid form was converted to lactone form as monitored by High Pressure Liquid Chromatography.
  • the broth was filtered and the mycelial cake was extracted with 12 L of toluene.
  • the toluene extract was washed with 1.5 L of 5 % w/v sodium bicarbonate solution and 1.5 L of demineralised water.
  • the washed toluene extract was concentrated under vacuum at about 50°C, to a volume of about 300-350 mL.
  • the concentrate was cooled to 5-7°C and stirred at this temperature for 3 hours.
  • the slurry was then filtered and the cake was washed with 100 mL of pre-cooled (5-10°C) toluene.
  • the wet cake was dried at 40°C under vacuum. 46.2 g of Lovastatin with a chromatographic purity of more than 95 % was obtained.
  • the whole broth was extracted with 7600 L of toluene.
  • the toluene extract was washed with 1340 L of 5 % w/v sodium bicarbonate solution and 670 L of demineralised water.
  • the washed toluene extract was concentrated under vacuum at 40 - 60°C, to a volume of approximately 200 L.
  • the concentrate was cooled to 5 - 8°C and stirred further for 2 hours.
  • the slurry was then filtered and the cake was washed with 130 L of pre-cooled (5-10°C) toluene.
  • the wet cake was dried to yield 45.3 Kg of Lovastatin with a chromatographic purity of more than 95 %.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation et d'isolation de lovastatine (substance hypolipaémique active) sous forme essentiellement pure avec une pureté d'au moins 95 %. Ledit procédé consiste à lactoniser l'acide mévinolinique en lovastatine dans un mileu totalement aqueux.
PCT/IB2001/001087 2000-06-30 2001-06-20 Procede d'isolation de lovastatine WO2002000615A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BR0112024-7A BR0112024A (pt) 2000-06-30 2001-06-20 Processo de separação da lovastatina
PL01359560A PL359560A1 (en) 2000-06-30 2001-06-20 Process for the isolation of lovastatin
AU2001264173A AU2001264173A1 (en) 2000-06-30 2001-06-20 Process for the isolation of lovastatin
CA002412566A CA2412566A1 (fr) 2000-06-30 2001-06-20 Procede d'isolation de lovastatine
EP01938499A EP1299340A4 (fr) 2000-06-30 2001-06-20 Procede d'isolation de lovastatine
US10/311,944 US7052886B2 (en) 2000-06-30 2001-06-20 Process for the isolation of lovastatin
HU0301423A HUP0301423A2 (hu) 2000-06-30 2001-06-20 Eljárás lovasztatin izolálására

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN630/DEL/2000 2000-06-30
IN630DE2000 IN192861B (fr) 2000-06-30 2000-06-30

Publications (2)

Publication Number Publication Date
WO2002000615A2 true WO2002000615A2 (fr) 2002-01-03
WO2002000615A3 WO2002000615A3 (fr) 2002-05-30

Family

ID=11097066

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2001/001087 WO2002000615A2 (fr) 2000-06-30 2001-06-20 Procede d'isolation de lovastatine

Country Status (10)

Country Link
US (1) US7052886B2 (fr)
EP (1) EP1299340A4 (fr)
AU (1) AU2001264173A1 (fr)
BR (1) BR0112024A (fr)
CA (1) CA2412566A1 (fr)
HU (1) HUP0301423A2 (fr)
IN (1) IN192861B (fr)
PL (1) PL359560A1 (fr)
WO (1) WO2002000615A2 (fr)
ZA (1) ZA200300006B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2204285A1 (es) * 2002-05-20 2004-04-16 Ercros Industrial, S.A. Procedimiento para el aislamiento y purificacion de lovastatina.
WO2005012279A1 (fr) * 2003-08-04 2005-02-10 Biocon Limited Procede de lactonisation
US7777056B2 (en) 2004-03-30 2010-08-17 Lupin Ltd. Method for manufacture of 4-hydroxy pyran-2-one derivatives
CN115947708A (zh) * 2022-12-20 2023-04-11 浙江天草生物科技股份有限公司 一种从红曲中分离高纯度酸式洛伐他汀的方法

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2325498T3 (es) * 2003-10-14 2009-09-07 Lupin Limited Procedimiento de fabricacion de lovastatina.
CN100451644C (zh) * 2005-12-19 2009-01-14 北京维信学知科技发展有限公司 一种血脂康胶囊的质量检测方法
EP2288378A4 (fr) * 2008-04-16 2011-12-14 Univ Utah Res Found Ciblage pharmacologique de malformation vasculaire
IN2009MU00380A (fr) * 2009-02-18 2010-04-02
CN102344426A (zh) * 2010-07-30 2012-02-08 北大方正集团有限公司 一种提取并纯化洛伐他汀的方法
CN102993145B (zh) * 2011-09-19 2015-06-03 北大方正集团有限公司 一种提取纯化洛伐他汀的方法
CN103172602B (zh) * 2011-12-22 2015-04-29 北大方正集团有限公司 一种纯化洛伐他汀的方法
CN103172603B (zh) * 2011-12-22 2014-12-17 北大方正集团有限公司 一种高选择性酯化处理洛伐他汀酸的洛伐他汀提取方法
CN102875505B (zh) * 2012-08-02 2015-08-05 丽珠集团新北江制药股份有限公司 一种美伐他汀的提取精制工艺
CN106518824B (zh) * 2016-09-30 2019-06-04 丽珠集团(宁夏)制药有限公司 一种洛伐他汀的提取工艺
CN106496174B (zh) * 2016-09-30 2019-06-04 丽珠集团(宁夏)制药有限公司 一种洛伐他汀的提取精制工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319039A (en) * 1979-06-15 1982-03-09 Merck & Co., Inc. Preparation of ammonium salt of hypocholesteremic fermentation product
US4432996A (en) * 1980-11-17 1984-02-21 Merck & Co., Inc. Hypocholesterolemic fermentation products and process of preparation
US5763646A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Process for manufacturing simvastatin from lovastatin or mevinolinic acid

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5925599B2 (ja) 1979-02-20 1984-06-19 三共株式会社 新生理活性物質モナコリンｋおよびその製造法
US4231938A (en) 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
US4282155A (en) 1980-02-04 1981-08-04 Merck & Co., Inc. Antihypercholesterolemic compounds
HU208997B (en) * 1992-06-17 1994-02-28 Gyogyszerkutato Intezet Microbiological method for producing mevinoline
SI9300303A (en) * 1993-06-08 1994-12-31 Krka Tovarna Zdravil Process for isolation of hypolipemic effective substance
CA2243592C (fr) 1995-12-06 2001-12-25 Antibiotic Co. Procede de production de lovastatine
SI9800046A (sl) * 1998-02-18 1999-08-31 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Postopek za pridobivanje inhibitorjev HMG-CoA reduktaze visoke čistosti
AU5705000A (en) 1999-06-29 2001-01-31 Kaneka Corporation Process for selective lactonization
US7194013B2 (en) * 2001-07-02 2007-03-20 Nichia Corporation GaN semiconductor laser device, and optical disk information system using the laser device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319039A (en) * 1979-06-15 1982-03-09 Merck & Co., Inc. Preparation of ammonium salt of hypocholesteremic fermentation product
US4432996A (en) * 1980-11-17 1984-02-21 Merck & Co., Inc. Hypocholesterolemic fermentation products and process of preparation
US5763646A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Process for manufacturing simvastatin from lovastatin or mevinolinic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1299340A2 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2204285A1 (es) * 2002-05-20 2004-04-16 Ercros Industrial, S.A. Procedimiento para el aislamiento y purificacion de lovastatina.
WO2005012279A1 (fr) * 2003-08-04 2005-02-10 Biocon Limited Procede de lactonisation
US7777056B2 (en) 2004-03-30 2010-08-17 Lupin Ltd. Method for manufacture of 4-hydroxy pyran-2-one derivatives
CN115947708A (zh) * 2022-12-20 2023-04-11 浙江天草生物科技股份有限公司 一种从红曲中分离高纯度酸式洛伐他汀的方法

Also Published As

Publication number Publication date
IN192861B (fr) 2004-05-22
HUP0301423A2 (hu) 2003-08-28
PL359560A1 (en) 2004-08-23
WO2002000615A3 (fr) 2002-05-30
EP1299340A2 (fr) 2003-04-09
AU2001264173A1 (en) 2002-01-08
US7052886B2 (en) 2006-05-30
CA2412566A1 (fr) 2002-01-03
BR0112024A (pt) 2003-09-09
US20030215932A1 (en) 2003-11-20
ZA200300006B (en) 2003-10-27
EP1299340A4 (fr) 2004-06-30

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